Pharmacovigilance and reproductive health: the Italian contribute to the results of the EUROmediCAT project

EUROmediCAT – “Safety of medication use in pregnancy”, a project of the Seventh Framework Programme for Research and Technical Development funded by the European Union in the period 2011-2015, experimented integrating “traditional” registers for congenital anomalies with other already existing healthcare databases to develop and evaluate a surveillance system on the safety of medications during pregnancy. Nine European partners participated to the projects, among which, as Italian partner, the Institute of Clinic Physiology of the CNR, Pisa.¹
Data from 15 registers for congenital anomalies of the European network for surveillance of congenital anomalies (EUROCAT) have been used, relative to 13 countries, plus data from 7 healthcare databases containing information on pharmaceutical prescriptions, relative to 5 countries. The central database included around 160,000 newborns with congenital anomalies, born alive or dead, and pregnancy interruptions for foetal anomalies, with more than 36,000 drugs exposition, relative to a population of 7.2 million of births between 1995 and 2002. The healthcare databases crossed with the registers for congenital anomalies referred to the period 2004-2010.² The project carried out case-control and cohort studies and analysed the exposition to four specific classes of medications: serotonergic antidepressants (SSRI), antiepileptics, antidiabetics and antiasthmatics.
The results relative to the use of SSRI show important treatment differences. Their use decreased everywhere starting from the trimester before the pregnancy, even though the general use of SSRI has been increasing since 2004 and it is very high in the United Kingdom. Italian women take the least antidepressants in pregnancy, with percentages equal to 1.6 in Tuscany and 1.2 in the Emilia-Romagna Region.³ A literature review highlighted 16 signals of congenital anomalies associated to the use of SSRI, among which congenital cardiac defects, some of which have been confirmed by the case-control and cohort studies.
Also for the antiepileptics, significant usage differences emerged among countries, even though for all of them the use during pregnancy is lower than the six previous months. In addition, the use of antiepileptics of new generation in respect to the ones of old generation, associated to a risk of congenital anomalies 2 or 3 times higher than general population, varies among European Countries. In Tuscany, there are 56 over 10,000 prescriptions during pregnancy and 44 over 10,000 in the Emilia-Romagna Region, whilst the European average value is 51 over 10,000. The percentages of prescriptions that are interrupted during pregnancy, instead of before the pregnancy, and the low prescriptions of folic acid during the periconceptional period suggest an elevate amount of non-programmed pregnancies or a periconceptional assistance (which should include the optimal choice of the medication) not yet adequate for many women.⁴
Antidiabetic prescriptions, both insulin and oral antidiabetics, have been increasing since 2004 and the use of insulin analogs has surpassed human insulins. The difference in the prescriptions of insulin during the third trimester of pregnancy between Tuscany (2.2%) and the Emilia-Romagna Region (0.8%), or other regions of the study, strikes. Presumably, it is due to the different screening policy of gestational diabetes implemented during the study period: the Tuscany Region offered free screening to all the women, whilst in the Emilia-Romagna Region, like in the rest of Europe, it was only for women at risk. A literature review did not show evidences of teratogenicity for insulin analogs. Also, the cohort study carried out confirmed insulin analogs do no increase the risk of congenital anomalies in respect to human insulin.
For antiasthmatics, the results interpretation is complex because of the effects of pregnancy on both the use of drugs and the severity of the disease. In Tuscany, an antiasthmatic was prescribed in 5.3% of the observed deliveries between 2004 and 2010, in respect to 8.4% registered in the Emilia-Romagna Region, whilst the percentage is higher in the United Kingdom (9.6%). The drugs most commonly used in all countries are beta 2 agonist inhalers and corticosteroids inhalers.⁵ A literature review highlighted 10 signals of specific congenital anomalies associated with the use of antiasthmatics. The case-control and cohort studies confirmed some signals (steroid inhalers with anal atresia) and confuted others (steroid inhalers and long acting beta 2 agonist inhalers, LABAs, with severe cardiopathies) but it is difficult to distinguish the effects of the medications from those due to asthma. The results demonstrated the importance of actively managing asthma avoiding the need of treating asthmatic crisis with high doses of drugs.⁶
The project revealed significant differences among the different countries for the use of the 4 classes of drugs and it is clear that the optimal risk-benefit evaluation is not known yet: only an accurate and prolonged period of study and surveillance will allow to establish the best strategies to offer to women. A specific online survey carried out during the project has also underlined the possibility of purchasing on the Internet teratogenic drugs like isotretinoin without prescription and with no information on the package about the documented teratogenicity of the drug.
EUROmediCAT showed that it is possible to use the existent databases and that a multidisciplinary collaboration is necessary to improve the safety of medications for women in reproductive age.
At its conclusion, the project disseminated 25 recommendations in order to optimise the use of the current data, networks and infrastructures in Europe to improve reproductive pharmacovigilance.⁷